More attractive is presently the hypothesis that, saquinavir-mediated up-regulation Saracatinib of c-Myc expression, could be the consequence of drug-induced proteosoma impairment [26], resulting in the failure of c-Myc protein degradation [31]. Indeed, the drug is able to reverse also the decline of c-Myc protein following siRNA- mediated “knock down”. In line with this hypothesis, beside to a c-Myc mediated increase of hTERT transcription, we cannot rule out also that reduction of protein degradation could be partially involved in saquinavir-induced hTERT up-regulation. Of particular interest is the finding that saquinavir-induced telomerase increase

was followed by increased proliferation rate in activated normal mononuclear cells [9]. On the contrary, as shown in the present study, cell growth impairment occurred when Jurkat leukemia cells were subjected to similar selleck kinase inhibitor experimental conditions. No data are presently available to identify the mechanism underlying the different responses to saquinavir between normal and malignant lymphoid cells. It is reasonable to assume that telomerase activity and cell proliferation can be disjointed processes differentially regulated in different types of cells.

For example, dichotomy between telomerase activity and proliferation was demonstrated in highly differentiated “old” CD8+T cells following PDL-1 signalling blockade [32]. In any case, the finding that saquinavir is able to augment telomerase activity Q-VD-Oph order could be considered a negative aspect of the pharmacological profile of this molecule in oncology. However, high levels of telomerase are constitutively expressed in the majority of malignant cells (reviewed in 13). Therefore, increase of telomerase expression should not modify substantially the already “immortal” phenotype produced by the basal levels of this enzyme complex in cancer cells [33]. On the other hand, large experimental evidence is now available showing

Adenosine triphosphate that hTERT could be involved in host’s immune responsiveness against autochtonous tumor. A number of HLA-restricted peptides can be generated following proteosomal-mediated degradation of hTERT protein. These peptides, presented by Class I HLA molecules on malignant cell surface elicit CD8+ T cell cytotoxic response of the host, leading to potentially efficient antitumor immunity (reviewed in 15, 16). It is reasonable to hypothesize that drug-induced up-regulation of hTERT could increase the probability of endocellular generation of hTERT-derived peptides showing the molecular pattern required for presentation in association with class I HLA gene products on the cell membrane of neoplastic cells. This would enhance, at least in principle, the level of host’s immune cytotoxic responsiveness against malignant cells.